The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. This research designs a region-confined PROTAC nanoplatform integrating ROS-activatable and hypoxia-responsive PRO-TAC prodrugs for precise manipulation of bromodomain and extra-terminal protein 4 expression and tumor eradication. These nanoparticles selectively accumulate in tumors, penetrating deeply via MMP-2 response. Photoactivity reactivates in acidic environments, releasing PROTAC due to ROS generated via photodynamic therapy in normoxic microenvironments. A hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. The nanoplatform effectively degrades BRD4 in both normoxic and hypoxic environments, hindering tumor progression in breast and head-neck tumor models.

Jing Gao, Xingyu Jiang, Shumin Lei, Wenhao Cheng, Yi Lai, Min Li, Lei Yang, Peifeng Liu, Xiao-hua Chen, Min Huang, Haijun Yu, Huixiong Xu, Zhiai Xu